Prognosis in clinical cancer is an area of great concern and interest. It is important to know the aggressiveness of the malignant cells and the likelihood of tumor recurrence in order to plan the most effective therapy. Breast cancer, for example, is managed by several alternative strategies. In some cases local-regional and systemic radiation therapy is utilized while in other cases mastectomy and chemotherapy or mastectomy and radiation therapy are employed. Current treatment decisions for individual breast cancer patients are frequently based on (1) the number of axillary lymph nodes involved with disease, (2) estrogen receptor and progesterone receptor status, (3) the size of the primary tumor, and (4) stage of disease at diagnosis (Clark et al. (1983) N. Engl. J. Med. 309: 1343). It has also been reported that DNA aneuploidy and proliferative rate (percent S-phase) can help in predicting the course of disease (Dressler et al. (1988) Cancer 61: 420); and Clark et al. (1989 N. Engl. J. Med. 320: 627). However, even with these additional factors, the course of disease for all breast cancer patients cannot generally be predicted.
Similarly, in the case of colorectal carcinoma, although approximately 70% of the patients with primary disease may undergo an apparently curative resection, 40% will develop recurrent disease within 5 years (McArdle et al. (1990) Br. J. Surg. 77: 280-282). Liver metastases are the major determinant of reduced survival (Finley and McArdle (1983) Gastroenterology 85: 596-599), however, it is still difficult to predict patients at risk.
Follow-up regimens after removal of primary cancers, in general, consist of interval history, physical examinations and surveillance (e.g., endoscopy, mammography, detection of molecular markers, etc.). While the surveillance of molecular markers offers a relatively convenient, non-invasive follow-up regimen, the prognostic value of a number of known markers is unresolved. For example, in the case of colorectal cancer, the utility of analysing consecutive serum carcinoembryonic antigen (CEA) levels has been questioned (Kievit and Van der Velde (1990) Cancer 65: 2580-2587; Virgo et al. (1995) JAMA 23: 1837-1841). Nevertheless, CEA is still used as an eventual predictor of residual disease or metastases (Lucha et al. (1997) Dis. Colon Rectum 40: 145-149).
In practice, however, identification of reliable markers for cancer detection and in particular for cancer prognosis has proved to be a difficult task. Certain released fragments and molecules may be rapidly cleared from circulation by the lymph nodes, liver and phagocytosis. Further, certain molecules are present in several different connective tissues, thus making correlation to metabolism in a particular tissue based on circulating levels of the molecule uncertain. Even where levels of a particular molecule can be traced to metabolism in the tissue of interest, the molecules may decline to undetectable levels or be biochemically altered in structure during particular stages of a disease.
Not surprisingly, therefore, attempts to develop assays, especially those utilizing serum, that correlate levels of certain proteins to cancer prognosis have met with mixed success.